U.S. patent application number 10/084035 was filed with the patent office on 2002-10-17 for tissue augmentation material and method.
Invention is credited to Devine, Timothy R., Hubbard, William G..
Application Number | 20020151466 10/084035 |
Document ID | / |
Family ID | 27569003 |
Filed Date | 2002-10-17 |
United States Patent
Application |
20020151466 |
Kind Code |
A1 |
Hubbard, William G. ; et
al. |
October 17, 2002 |
Tissue augmentation material and method
Abstract
A permanent, biocompatible material for soft tissue
augmentation. The biocompatible material comprises a matrix of
smooth, round, finely divided, substantially spherical particles of
a biocompatible ceramic material, close to or in contact with each
other, which provide a scaffold or lattice for autogenous, three
dimensional, randomly oriented, non-scar soft tissue growth at the
augmentation site. The augmentation material can be homogeneously
suspended in a biocompatible, resorbable lubricious gel carrier
comprising a polysaccharide. This serves to improve the delivery of
the augmentation material by injection to the tissue site where
augmentation is desired. The augmentation material is especially
suitable for urethral sphincter augmentation, for treatment of
incontinence, for filling soft tissue voids, for creating soft
tissue blebs, for the treatment of unilateral vocal cord paralysis,
and for mammary implants. It can be injected intradermally,
subcutaneously or can be implanted.
Inventors: |
Hubbard, William G.;
(Burlington, WI) ; Devine, Timothy R.; (Whitefish
Bay, WI) |
Correspondence
Address: |
Michael D. Rechtin
Foley & Lardner
Suite 3300
330 North Wabash Avenue
Chicago
IL
60611-3608
US
|
Family ID: |
27569003 |
Appl. No.: |
10/084035 |
Filed: |
February 27, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10084035 |
Feb 27, 2002 |
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09626326 |
Jul 26, 2000 |
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10084035 |
Feb 27, 2002 |
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09288999 |
Aug 4, 1998 |
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09288999 |
Aug 4, 1998 |
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08538444 |
Oct 3, 1995 |
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5922025 |
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08538444 |
Oct 3, 1995 |
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08159071 |
Nov 29, 1993 |
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08159071 |
Nov 29, 1993 |
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07999411 |
Jan 21, 1993 |
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07999411 |
Jan 21, 1993 |
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07833874 |
Feb 11, 1992 |
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60148590 |
Aug 13, 1999 |
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Current U.S.
Class: |
435/6.16 ; 514/1;
514/54 |
Current CPC
Class: |
C04B 35/636 20130101;
C04B 35/6365 20130101; A61L 27/46 20130101; A61L 27/46 20130101;
C08L 1/26 20130101; C08L 5/00 20130101; A61L 27/50 20130101; C04B
35/447 20130101; A61L 27/446 20130101; A61L 27/52 20130101; A61L
2400/06 20130101; A61L 27/46 20130101; A61L 27/10 20130101; A61F
2/0036 20130101 |
Class at
Publication: |
514/2 ; 514/54;
514/1 |
International
Class: |
A61K 038/18; A61K
031/715 |
Claims
What is claimed:
1. A tissue augmentation composition, comprising: a biomaterial for
augmenting a desired tissue site; a biocompatible, resorbable,
lubricous carrier for homogeneously suspending the biomaterial both
prior to and during the introduction of the composition to the
desired tissue site; and a pharmaceutically active agent disposed
in the carrier, wherein the carrier comprises a polysaccharide gel
having a viscosity between about 20,000 centipoise and about
350,000 centipoise.
2. The tissue augmentation composition of claim 1, wherein the
carrier comprises a polysaccharide gel having a viscosity between
about 150,000 centipoise to about 250,000 centipoise.
3. The tissue augmentation composition of claim 2, wherein the
carrier comprises a polysaccharide gel having a viscosity between
about 200,000 centipoise to about 250,000 centipoise.
4. The tissue augmentation composition of claim 1, wherein the
pharmaceutically active agent comprises a growth factor.
5. The tissue augmentation composition of claim 1, wherein the
pharmaceutically active agent comprises an antibiotic.
6. The tissue augmentation composition of claim 1, wherein the
pharmaceutically active agent comprises an analgesic.
7. The tissue augmentation composition of claim 1, further
comprising an additive.
8. The tissue augmentation composition of claim 7, wherein the
additive comprises at least one of a surfactant, a stabilizer, and
a pH buffer.
9. The tissue augmentation composition of claim 1, wherein the
biomaterial comprises a material selected from the group consisting
of a ceramic, polymethylmethacrylate, glass, a metal, silicone and
mixtures thereof.
10. The tissue augmentation composition of claim 9, wherein the
metal comprises titanium.
11. The tissue augmentation composition of claim 1, wherein the
desired tissue site is a soft tissue site.
12. The tissue augmentation composition of claim 1, wherein the
composition is implantable into the human body, and wherein carrier
maintains its viscous and elastic properties after
implantation.
13. The tissue augmentation composition of claim 1, wherein the
desired tissue site is a hard tissue site.
14. The tissue augmentation composition according to claim 14,
wherein the desired tissue site is an osseous site.
15. The tissue augmentation composition according to claim 15,
wherein the desired tissue site is an osseous site in a state of
osteoporosis.
16. The tissue augmentation composition according to claim 1,
wherein the carrier maintains its elastic characteristics after the
forming of the composition.
17. The tissue augmentation composition of claim 1, wherein the
polysaccharide gel comprises a polysaccharide selected from the
group consisting of a cellulose polysaccharide, starch, chitin,
chitosan, hyaluronic acid, hydrophobe modified polysaccharide, an
alginate, a carrageenan, agar, agarose, an intramolecular complex
of a polysaccharide, an oligosaccharide and a macrocylic
polysaccharide.
18. A composition for homogeneously suspending a biomaterial prior
and during introduction of the biomaterial to a desired tissue
site, the composition comprising: a biocompatible, resorbable,
lubricous carrier including a polysaccharide gel having a viscosity
between about 20,000 centipoise and about 350,000 centipoise; and a
pharmaceutically active agent disposed in the carrier.
19. The composition of claim 18, wherein the carrier comprises a
polysaccharide gel having a viscosity between about 150,000
centipoise to about 250,000 centipoise.
20. The composition of claim 18, wherein the pharmaceutically
active agent is selected from the group consisting of a growth
factor, an antibiotic and an alalgesic.
21. The tissue augmentation composition of claim 18, further
comprising an additive.
22. The composition of claim 18, wherein the biomaterial comprises
a material selected from the group consisting of a ceramic,
polymethylmethacrylate, glass, a metal, silicone and mixtures
thereof.
23. The composition of claim 18, wherein the desired tissue site is
a hard tissue site.
24. The composition of claim 18, wherein the desired tissue site is
a soft tissue site.
25. In a biocompatible composition for augmenting tissue, the
composition comprising a biomaterial for augmenting tissue and a
biocompatible, resorbable, lubricous carrier, the improvement
comprising a polysaccharide gel carrier having a viscosity between
about 20,000 centipoise to about 350,000 centipoise and further
including a pharmaceutically active agent disposed in the carrier,
the carrier also homogeneously suspending the biomaterial in the
composition prior to and during the introduction of the composition
to a desired tissue site.
26. The composition of claim 26, wherein the carrier comprises a
polysaccharide gel having a viscosity between about 200,000
centipoise to about 250,000 centipoise.
27. The composition of claim 26, further comprising an
additive.
28. The composition of claim 28, wherein the additive comprises at
least one of a surfactant, a stabilizer, and a pH buffer.
29. The composition of claim 26, wherein the pharmaceutically
active agent comprises at least one of a analgesic, an antibiotic
and a growth factor.
30. The composition of claim 26, wherein the biomaterial comprises
a material selected from the group consisting of a ceramic,
polymethylmethacrylate, glass, a metal, silicone and mixtures
thereof.
31. The composition of claim 26, wherein the composition is
implantable into the human body, and wherein carrier maintains its
viscous and elastic properties after implantation.
32. The composition of claim 26, wherein the desired tissue site is
a hard tissue site.
33. The composition of claim 26, wherein the desired tissue site is
a soft tissue site.
34. A substantially dehydrated biocompatible tissue augmentation
composition, comprising: a biomaterial for augmenting a desired
tissue site; a dehydrated, biocompatible, resorbable, suspending
medium; and a pharmaceutically active agent, wherein the suspending
medium includes a dehydrated polysaccharide gel for maintaining the
biomaterial suspended in the composition.
35. The composition of claim 35, wherein the pharmaceutically
active agent comprises at least one of a growth factor, an
antibiotic and an analgesic.
36. The composition of claim 35, wherein the biomaterial is
selected from the group consisting of a ceramic, a plastic, and a
metal.
37. The composition of claim 37, wherein the biomaterial comprises
rounded, substantially spherical, biocompatible, substantially
nonresorbable, finely divided ceramic particles.
38. The composition of claim 38, wherein the ceramic particles are
selected from the group consisting of calcium phosphate particles,
calcium silicate particles, calcium carbonate particles and alumina
particles.
39. The composition of claim 35, further comprising an
additive.
40. The composition of claim 35, wherein the composition is capable
cut or shaped.
Description
[0001] This application in a continuation of U.S. patent
application Ser. No. 09/626,326, filed Jul. 26, 2000, which is a
conversion from Provisional Application No. 60/148,590, filed Aug.
13, 1999. U.S. patent application Ser. No. 09/626,326 is also a
continuation-in-part of Application No. 09/288,999, filed Aug. 4,
1998, which is a continuation of Application Ser. No. 08/538,444,
filed on Oct. 3, 1995 and issued on Jul. 13, 1999 as U.S. Pat. No.
5,922,025, which is a division of Application Ser. No. 08/159,071,
filed Nov. 29, 1993, which is a file wrapper continuation of
Application Ser. No. 07/999,411, filed Jan. 21, 1993, abandoned,
which is a continuation-in-part of Application Ser. No. 07/833,874,
filed Feb. 11, 1992, abandoned.
FIELD OF THE INVENTION
[0002] This invention relates to biocompatible compositions for
soft tissue augmentation more specifically urethral sphincter
augmentation for treatment of incontinence, for filling soft tissue
voids or creating soft tissue blebs, for mammary implants, and for
the treatment of unilateral vocal cord paralysis. This invention
also relates to a gel carrier for the biocompatible
compositions.
BACKGROUND OF THE INVENTION
[0003] Examples of biocompatible materials that have been proposed
for use in augmenting soft tissue in the practice of plastic and
reconstructive surgery, include collagen, gelatin beads, beads of
natural or synthetic polymers such as polytetrafluoroethylene,
silicone rubber and various hydrogel polymers, such as
polyacrylonitrile-polyacrylamide hydrogels.
[0004] Most often, the biomaterials are delivered to the tissue
site where augmentation is desired by means of an injectable
composition which comprises the biomaterial and a biocompatible
fluid that acts as a lubricant to improve the injectability of the
biomaterial suspension. The injectable biomaterial compositions can
be introduced into the tissue site by injection from a syringe
intradermally or subcutaneously into humans or other mammals to
augment soft tissue, to correct congenital anomalies, acquired
defects or cosmetic defects. They may also be injected into
internal tissues such as tissue defining sphincters to augment such
tissue in the treatment of incontinence, and for the treatment of
unilateral vocal cord paralysis.
[0005] U.K Patent Application No. 2,227,176 to Ersek et al, relates
to a microimplantation method for filling depressed scars,
unsymmetrical orbital floors and superficial bone defects in
reconstructive surgery procedures using microparticles of about 20
to 3,000 microns which may be injected with an appropriate
physiologic vehicle and hypodermic needle and syringe in a
predetermined locus such as the base of depressed scars, beneath
skin areas of depression and beneath perichondrium or periosteum in
surface irregularities of bone and cartilage. Textured
microparticles can be used, including silicone,
polytetrafluoroethylene, ceramics or other inert substances. In
those instances wherein the requirement is for hard substances,
biocompatible material such as calcium salts including
hydroxyapatite or crystalline materials, biocompatible ceramics,
biocompatible metals such as stainless steel particles or glass may
be utilized. Appropriate physiological vehicles have been
suggested, including saline, various starches, polysaccharides, and
organic oils or fluids.
[0006] U.S. Pat. No. 4,803,075 to Wallace et al, relates to an
injectable implant composition for soft tissue augmentation
comprising an aqueous suspension of a particulate biocompatible
natural or synthetic polymer and a lubricant to improve the
injectability of the biomaterial suspension.
[0007] U.S. Pat. No. 4,837,285 to Berg et al, relates to a
collagen-based composition for augmenting soft tissue repair,
wherein the collagen is in the form of resorbable matrix beads
having an average pore size of about 50 to 350 microns, with the
collagen comprising up to about 10% by volume of the beads.
[0008] U.S. Pat. No. 4,280,954 to Yannas et al, relates to a
collagen-based composition for surgical use formed by contacting
collagen with a mucopolysaccharide under conditions at which they
form a reaction product and subsequently covalently crosslinking
the reaction product.
[0009] U.S. Pat. No. 4,352,883 to Lim discloses a method for
encapsulating a core material, in the form of living tissue or
individual cells, by forming a capsule of polysaccharide gums which
can be gelled to form a shape retaining mass by being exposed to a
change in conditions such as a pH change or by being exposed to
multivalent cations such as calcium.
[0010] Namiki, "Application of Teflon.RTM. Paste for Urinary
Incontinence-Report of Two Cases," Urol. Int., Vol. 39, pp.
280-282, (1984), discloses the use of a polytetrafluoroethylene
paste injection in the subdermal area to treat urinary
incontinence.
[0011] Drobeck et al, "Histologic Observation of Soft Tissue
Responses to Implanted, Multifaceted Particles and Discs of
Hydroxylapatite," Journal of Oral Maxillofacial Surgery, Vol. 42,
pp. 143-149, (1984), discloses that the effects on soft tissue of
long and short term implants of ceramic hydroxylapatite implanted
subcutaneously in rats and subcutaneously and subperiosteally in
dogs. The inventions consisted of implanting hydroxylapatite in
various sizes and shapes for time periods ranging from seven days
to six years to determine whether migration and/or inflammation
occurred.
[0012] Misiek et al., "Soft Tissue Responses to Hydroxylapatite
Particles of Different Shapes," Journal of Oral Maxillofacial
Surgery, Vol. 42, pp. 150-160, (1984), discloses that the
implantation of hydroxylapatite in the form of sharp edged
particles or rounded particles in the buccal soft tissue pouches
produced inflammatory response at the implant sites with both
particle shapes. Each of the particles weighed 0.5 grams. However,
inflammation resolved at a faster rate at the sites implanted with
the rounded hydroxylapatite particles.
[0013] Shimizu, "Subcutaneous Tissue Responses in Rats to Injection
of Fine Particles of Synthetic Hydroxyapatite Ceramic," Biomedical
Research, Vol. 9, No. 2, pp. 95-111 (1988), discloses that
subcutaneous injections of fine particles of hydroxyapatite ranging
in diameter from about 0.65 to a few microns and scattered in the
tissue were phagocytized by macrophages in extremely early stages.
In contrast, larger particles measuring several microns in diameter
were not phagocytized, but were surrounded by numerous macrophages
and multinucleated giant cells. It was also observed that the small
tissue responses to hydroxyapatite particles were essentially a
non-specific foreign body reaction without any cell or tissue
damage.
[0014] R. A. Appell, "The Artificial Urinary Sphincter and
Periurethral Injections," Obstetrics and Gynecology Report Retort
Vol. 2, No. 3, pp. 334-342, (1990), is a survey article disclosing
various means of treating urethral sphincteric incompetence,
including the use of injectables such as polytetrafluoroethylene
micropolymer particles of about 4 to 100 microns in size in
irregular shapes, with glycerin and polysorbate. Another
periurethral injectable means consists of highly purified bovine
dermal collagen that is crosslinked with glutaraldehyde and
dispersed in phosphate-buffered physiologic saline.
[0015] Politano et al, "Periurethral Teflon.RTM.Injection for
Urinary Incontinence," The Journal of Urology, Vol. 111, pp.
180-183 (1974), discloses the use of Polytetrafluoroethylene paste
injected into the urethra and the periurethral tissues to add bulk
to these tissues to restore urinary control in both female and male
patients having urinary incontinence.
[0016] Malizia et al, "Migration and Granulomatous Reaction After
Periurethral Injection of Polytef (Teflon.RTM.)," Journal of the
American Medical Association, Vol. 251, No. 24, pp. 3277-3281, Jun.
22-29 (1984), discloses that although patients with urinary
incontinence have been treated successfully by periurethral
injection of polytetrafluoroethylene paste, a study in continent
animals demonstrates migration of the polytetrafluoroethylene
particles from the inspection site.
[0017] Claes et al, "Pulmonary Migration Following Periurethral
Polytetrafluoroethylene Injection for Urinary Incontinence," The
Journal of Urology, Vol. 142, pp. 821-22, (September 1989),
confirms the finding of Malizia in reporting a case of clinically
significant migration of polytetrafluoroethylene paste particles to
the lungs after periurethral injection.
[0018] Ersek et al, "Bioplastique: A New Textured Copolymer
Microparticle Promises Pennanence in Soft-Tissue Augmentation,"
Plastic and Reconstructive Surgery, Vol. 87, No. 4, pp. 693-702,
(April 1991), discloses the use of a biphasic copolymer made of
fully polymerized and vulcanized methylmethylpolysiloxane mixed
with a plasdone hydrogel, and used in reconstructing cleft lips,
depressed scars of chicken pox and indentations resulting from
liposuction, glabella frown wrinkles and soft tissue augmentation
of thin lips. The biphasic copolymer particles were found to
neither migrate nor become absorbed by the body were textured and
had particle sizes varying from 100 to 600 microns.
[0019] Lemperle et al. "PMMA Microspheres for Intradermal
Implantation: Part I. Animal Research," Annals of Plastic Surgery,
Vol. 26, No. 1, pp. 57-63, (1991), discloses the use of
polymethylmethacrylate microspheres having particle sizes of 10 to
63 microns in diameter used for correction of small deficiencies
within the dermal corium to treat wrinkles and acne scars.
[0020] Kresa et al, "Hydron Gel Implants in Vocal Cords,"
Otolarynology Head and Neck Surgery, Vol. 98. No. 3, pp. 242-245,
(March 1988), discloses a method for treating vocal cord adjustment
where there is insufficient closure of the glottis which comprises
introducing a shaped implant of a hydrophilic gel that has been
previously dried to a glassy, hard state, into the vocal cord.
[0021] Hirano et al, "Transcutaneous Intrafold Injection for
Unilateral Vocal Cord Paralysis: Functional Results," Ann. Otol.
Rhinol. Laryngol., Vol. 99, pp. 598-604 (1990), discloses the
technique of transcutaneous intrafold silicone injection in
treating glottic incompetence caused by unilateral vocal fold
paralysis. The silicone injection is given under a local anesthetic
with the patient in a supine position, wherein the needle is
inserted through the cricothyroid space.
[0022] Hill et al, "Autologous Fat Injection for Vocal Cord
Medialization in the Canine Larynx," Laryngoscope, Vol. 101, pp.
344-348 (April 1991), discloses the use of autologous fat as an
alternative to Teflon.RTM.collagen as the implantable material in
vocal cord medialization, with a view to its use as an alternative
to non-autologous injectable material in vocal cord
augmentation.
[0023] Mikaelian et al, "Lipoinjection for Unilateral Vocal Cord
Paralysis," Laryngoscope, Vol. 101, pp. 4654-68 (May 1991),
discloses that the commonly used procedure of injecting
Teflon.RTM.paste to improve the caliber of voice in unilateral
vocal cord paralysis has a number of drawbacks, including
respiratory obstruction from overinjected Teflon.RTM. and
unsatisfactory voice quality. In this procedure, lipoinjection of
fat commonly obtained from the abdominal wall appears to impart a
soft bulkiness to the injected cord while allowing it to retain its
vibratory qualities. The injected fat is an autologous material
which can be retrieved if excessively overinjected.
[0024] Strasnick et al, "Transcutaneous Teflon.RTM. Injection for
Unilateral Vocal Cord Paralysis: An Update," Laryngoscope, Vol.
101, pp. 785-787 (July 1991), discloses the procedure of
Teflon.RTM. injection to restore glottic competence in cases of
paralytic dysphonia.
SUMMARY OF THE INVENTION
[0025] In accordance with the present invention, there is provided
a permanent, biocompatible material for soft tissue augmentation,
and methods for its use. There is also provided in accordance with
the present invention a gel carrier which is particularly
advantageous for the administration of the biocompatible material
to the desired tissue augmentation site.
[0026] The biocompatible material comprises a matrix of smooth,
rounded, substantially spherical, finely divided particles of a
biocompatible ceramic material, close to or in contact with each
other, which provide a scaffold or lattice for autogenous, three
dimensional, randomly oriented, non-scar soft tissue growth at the
augmentation site. The augmentation material can be homogeneously
suspended, for example, in a biocompatible, resorbable lubricious
gel carrier comprising, e.g., a polysaccharide. This serves to
improve the delivery of the augmentation material by injection to
the tissue site where augmentation is desired. The augmentation
material is especially suitable for urethral sphincter
augmentation, for treatment of incontinence, for filling soft
tissue voids, for creating soft tissue blebs, for the treatment of
unilateral vocal cord paralysis, and for mammary implants. It can
be injected intradermally or subcutaneously or can be
implanted.
DESCRIPTION OF THE DRAWINGS
[0027] In the accompanying drawings,
[0028] FIG. 1 is a photomicrograph of smooth, round calcium
hydroxyapatite particles at 40.times. magnification;
[0029] FIG. 2 is a photomicrograph of a histological section of
rabbit tissue at 50.times. magnification showing fibroblastic
infiltration.
[0030] FIG. 3 is a graph of the viscosity of the gel and
augmentation media both before and after sterilization.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0031] In instances of urinary incontinence, such as stress
incontinence in women, or after a prostatectomy in men, it is
necessary to compress the urethra to assist the sphincter muscle in
closing to avoid leakage of urine from the bladder.
[0032] The soft tissue augmentation material of the present
invention comprises an injection system which can be used to add
bulk and localize compression to the sphincter muscle/urethra,
thereby reducing the lumen size through one or more injections of
the augmentation material and thus substantially reduce or
eliminate urinary stress incontinence due to incompetent sphincters
in females and males.
[0033] The augmentation material can also be used in filling and
smoothing out soft tissue defects such as pock marks or scars.
Further use for the augmentation material can be for intracordal
injections of the laryngeal voice generator by changing the shape
of this soft tissue mass. The procedure involves delivering the
augmentation material to the site of treatment, preferably by
injection. The augmentation material or gel can also be used for
mammary implants.
[0034] The inventive augmentation material comprises smooth
rounded, substantially spherical, particles of a ceramic material.
The term "substantially spherical" refers to the fact that while
some of the present particles may be spheres, most of the particles
of the present invention are sphere-like in their shape, i.e., they
are spheroidal. FIG. 1 is illustrative of these spheroidal or
substantially spherical characteristics. The terms "rounded" or
"smooth, rounded" as used herein refers to the fact even though the
present particles are not perfect spheres, they do not have any
sharp or angular edges. The particles must be sufficiently large so
as to avoid phagocytosis, as is further discussed below. As an
upper limit the particles can be any size suitable for the desired
soft tissue augmentation. However, it is understood that for
introduction by injection the upper limit on particle size will be
dictated by the particular injection equipment employed. That is,
the particles must be sufficiently small so as to avoid aggregation
and clogging of the syringe when being injected. A typical range
for injection is from about 35 to 150 microns, preferably in a
narrow particle size range extending not more than about 35
microns, and more preferably extending not more than about 10 to 30
microns, and-most preferably having substantially equivalent
particle sizes. For example, the ceramic material can have a
uniform particle size distribution of about 35 to 65 microns, or 75
to 100 microns or 100 to 125 microns. These are meant to be
exemplary and not limiting. Other narrow particle size ranges
within the overall size range of 35 to 150 microns can also be
used. In discussing these ranges, it should be understood that as a
practical matter, a small amount of particles outside the desired
range may be present in a sample of the present augmentation
material. However, most of the particles in any given sample should
be within the desired range. Preferably, 90% of the particles are
within the desired range and most preferably 95-99% are within the
range.
[0035] The finely divided ceramic augmentation material is
substantially non-resorbable so that repetitious corrections are
not necessary. By substantially non-resorbable" is meant that
although some dissolution of the augmentation material may take
place over time, it is sufficiently slow so as to allow for
replacement with growing tissue cells. There is no antigenic
response because there are no amino acids as in collagen and
fibrinogen. The ceramic material is highly biocompatible and can be
injected through an 18 gauge or smaller opening syringe.
[0036] The preferred ceramic material is calcium hydroxyapatite,
also known as basic calcium orthophosphate, or calcium
hydroxylapatite, and is the natural mineral phase of teeth and
bones. As an implant material, granular calcium hydroxyapatite,
which is a sintered polycrystalline composite of calcium phosphate,
has proven to be highly compatible in tissue.
[0037] One method for preparing dense, rounded or substantially
spherical ceramic particles such as calcium hydroxyapatite is by
spray drying a slurry of about 20 to 40 weight % submicron particle
size calcium hydroxyapatite. This material is commercially
available or can be prepared by means known in the art such as by
low temperature crystallization methods, hydrothermal
crystallization methods, solid-solid reaction and the like. The
slurry can also include processing additives such as wetting agents
and binders, on the order of about 1 to 5 weight %. Suitable
wetting agents include polysorbate, sodium oxalate, ammonium
polyelectrolyte. Suitable binders include polyvinyl alcohol,
dextrin or carbowax.
[0038] The slurry is spray dried by pumping it through a nozzle to
form globules that are forced through a column of heated air to
remove the moisture. The agglomerated particles dry in
substantially spherical shape and are collected at one end of the
heated column.
[0039] The substantially spherical particles are then sintered in a
crucible at temperatures of about 1050 to 1200.degree. C. for at
least one hour. To minimize further agglomeration, a presintering
operation at about 800 to 1000.degree. C. for about one hour can be
employed.
[0040] After the presintering operation, the globular particles can
be agitated or rolled to prevent the individual particles from
sticking or clumping together. A rotary calcining furnace can be
used for this purpose. This type of furnace rotates so that the
agglomerated particles roll over one is another during the
sintering process thereby minimizing the clumping together of the
particles. A commercial source of such spray dried particles is
CeraMed Corp., Lakewood, Colo.
[0041] An alternative method for forming dense, spherical particles
is by rotary agglomeration, wherein the fine, submicron ceramic
particles, such as calcium hydroxyapatite, are placed on a large
diameter rotating bowl that is at least about 3 feet in
diameter.
[0042] The bowl is rotated on its axis at an angle of approximately
thirty degrees, with its speed and angle of rotation adjusted so
that the submicron particles roll across the face of the bowl. A
fine spray of binder solution, such as those described above, is
then sprayed on the particles at a rate which just wets the
particles. The rolling action across the face of the bowl and the
addition of the binder solution causes the particles to form small
rolling agglomerates that grow in size as the operation continues.
The operation is comparable to forming a large ball of snow by
rolling a small snowball down a hill. The operating conditions,
such as the size of bowl, speed of rotation, angle of rotation and
amount of spray used which define the size and density of the
agglomerates formed, are well known to those skilled in the art.
The agglomerated spherical particles can then be sintered in a
manner similar to the spray dried agglomerates.
[0043] The resulting sintered spherical particles can then be
separated and classified by size by means of well known sieving
operations through specifically sized mesh screens. The particle
size distribution and density can also be evaluated to ensure
suitability for a particular application. A commercial source of
such rotary agglomerated particles is CAM Implants, Leiden, The
Netherlands.
[0044] Further surface refining or smoothing can be accomplished by
a milling operation, such as ball milling. Extra mini-grinding
media can be used, but to minimize contamination, the spherical
particles can be milled on themselves. This can be done in a
standard jar mill or an inclined rotation mill by adding sufficient
amounts of purified water to the particles to ensure that the
particles roll evenly over each other. This can be done for long
periods such as several days to make the surface smooth on the
round agglomerates. If the starting agglomerates are not round,
they can be made smooth but not round by rolling. Irregularly
shaped agglomerates, although having a smooth surface, can jam,
obstruct or significantly increase the injection force on a syringe
needle when injected into tissue.
[0045] The agglomerated spherical particles can also be washed free
of small particles by using an inclined rotation mill. This can be
done by placing the agglomerates in the mill with purified water
and rolled for a sufficient time, such as one hour. The supernate
is then poured off and more purified water is added. The process is
repeated until the supernate is relatively clear after a rotating
cycle, and usually takes about three or four operations.
[0046] The methods described above are suitable for any ceramic
materials which may be employed.
[0047] A smooth surface on the individual round, spherical
particles is important to reduce and minimize surface porosity.
Surface smoothness can be improved by finishing operations known in
the art, such as surface milling and the like. It is preferred that
such smoothing operations be capable of minimizing surface
irregularities on the individual particles so that the surface
appears similar to that of a smooth round bead when viewed under a
microscope at 40.times. magnification. This is apparent from FIG.
1, which is a photomicrograph of calcium hydroxyapatite particles
having a particle size distribution of 38 to 63 microns. The
smooth, round substantially spherical and non-porous surface is
readily evident.
[0048] The ceramic particles are preferably smooth, hard, rounded
particles, having a density on the order of about 75 to 100%, and
preferably about 95 to 100% of the theoretical density of desired
ceramic material, e.g., calcium hydroxyapatite. The finishing
operations can also minimize the surface porosity of the calcium
hydroxyapatite particles to less than about 30%, and preferably
less than about 10%. This is preferred, because by minimizing
surface porosity, particles with smooth surfaces can be obtained,
thereby eliminating jagged, irregular surfaces and maximizing the
ability of the smooth, round particles to flow easily in contact
with each other.
[0049] Although this invention is described in terms of calcium
hydroxyapatite, other suitable materials useful herein include, but
are not limited to, calcium phosphate-based materials,
alumina-based materials and the like. Examples include, but are not
limited to, tetracalcium phosphate, calcium pyrophosphate,
tricalcium phosphate, octacalcium phosphate, calcium fluorapatite,
calcium carbonate apatite, and combinations thereof. Other
equivalent calcium based compositions can also be used such as
calcium carbonate, and the like.
[0050] As noted, the individual ceramic particles used in the
present invention have a generally smooth, round, preferably
spherical shape, in contrast to particles with more textured porous
surfaces or openings, and having jagged, irregular shapes or shapes
with straight edges. The smooth round shape enables the ceramic
particles to be more easily extruded and to flow with reduced
friction from a syringe into the tissue site where soft tissue
augmentation is desired. Once at the tissue site, the ceramic
particles provide a matrix or scaffolding for autogenous tissue
growth.
[0051] As mentioned above, particle sizes in the range of about 35
to 150 microns are optimal to minimize the possibility of particle
migration by phagocytosis and to facilitate injectability.
Phagocytosis occurs where smaller particles on the order of 15
microns or less become engulfed by the cells and removed by the
lymphatic system from the site where the augmentation material has
been introduced into the tissues, generally by injection.
[0052] At the lower end, particles greater than 15 microns and
typically 35 microns or above are too large to be phagocytosized,
and can be easily separated by known sizing techniques. Thus, it is
relatively simple to produce the narrow or equivalent particle size
ranges that are most desirable for use in this invention.
[0053] It is also desirable to use a narrow or equivalent particle
size range of ceramic particles due to the fact that a distribution
of such smooth, round, substantially spherical particles reduces
friction, and facilitates the ease of injecting the particles by
needle from a syringe into the skin tissue at the desired
augmentation site. This is in contrast to the use of the more
porous, textured, irregularly shaped particles which tend to
increase the frictional forces, and are much more difficult to
deliver by injection.
[0054] As discussed above, the particle size distribution, or range
of particle sizes of the ceramic material within the overall range
of 35 to 150 microns is preferably minimized to a more narrow or
equivalent particle size range. This maximizes the intraparticle
void volume, or interstitial volume, into which autogenous tissue
growth, stimulated by the presence of the augmentation material,
can occur. A greater interstitial volume exists between particles
that are equivalent in size, compared with particles having a
variable size distribution. In the context of this invention, the
interstitial volume is the void space existing between particles of
the augmentation material that are close to or in contact with each
other.
[0055] For example, in crystalline lattice structures such as face
centered cubic, body centered cubic and simple cubic, the
percentage of interstitial void space, known as the atomic packing
factor, is 26%, 33%, and 48%, respectively. This is independent of
the diameter of the atom or in this case, the particle. Since the
ceramic particles never pack as tightly as the atoms in a
crystalline lattice structure, the void volume would be even
greater, thereby maximizing the growth of autogenous tissue.
[0056] To extend the analogy of the crystalline structure a step
further, the interstitial opening defines the maximum size that a
particle can fit into a normally occurring void space in the
structure. The largest interstitial space is about 0.4 times the
size of the mean ceramic particle in the particle size
distribution.
[0057] Thus, if the particle size distribution is about 35 to 65
microns, the mean particle size would be 50 microns. The largest
interstitial space would be 50.times.0.4=20 microns. Since no 20
micron size particles exist in the distribution, packing would be
minimized. Similarly, with a particle size distribution of 75 to
125 microns, the mean particle size is 100 microns, and the largest
interstitial space would be 100.times.0.4=40 microns. Since no 40
micron particles exist in the distribution, packing would also be
minimized. Therefore, if the ceramic particles are restricted to a
narrow particle size range or equivalent size distribution, there
will be a maximizing of the void volume into which the is
autogenous tissue can grow.
[0058] Other suitable particle size distribution ranges include 35
to 40 microns, 62 to 74 microns and 125 to 149 microns, however,
any other correspondingly narrow ranges can also be used.
[0059] In contrast, where there is a wide particle size
distribution, there is a greater tendency for the particles to
become densely packed since the smaller particles tend to group or
migrate into the spaces between the larger particles. This results
in less interstitial space available between the particles for the
autogenous tissue such as fibroblasts and chondroblasts to
infiltrate and grow.
[0060] The tissue growth where the augmentation material has a wide
particle size distribution is denser and harder, because of the
packing effect which occurs between the large and small particles.
In contrast, the use of particles equivalent in size, or having a
narrow particle size range of uniformly distributed particles
increases the intraparticle void volume. This enables a maximum
amount of autogenous or three dimensional randomly oriented
non-scar soft tissue in growth to infiltrate the space or
interstices between the particles. The more interstitial space that
is available makes it more likely that the subsequent autogenous
tissue growth stimulated by the presence of the augmentation
material into the matrix or scaffolding provided by the
augmentation material will closely resemble the original tissue in
the immediate vicinity or locus of augmentation.
[0061] The process of soft tissue augmentation can occur by
injecting or implanting the biocompatible augmentation material
comprising the desired particle sizes of the desired ceramic
material into the tissue at the desired augmentation site to form a
bleb or blister. The subsequent autogenous tissue growth into the
matrix provided by the augmentation material will most closely
resemble the surrounding tissue in texture and properties. This is
in contrast to that which occurs using known state-of the-art
procedures, where foreign body response is known to occur,
typically with Teflon.RTM. augmentation where granulomas have been
known to form.
[0062] Foreign body response is the body reaction to a foreign
material. A typical foreign body tissue response is the appearance
of polymorphonuclear leukocytes near the material followed by
macrophages. If the material is nonbioreactive, such as silicone,
only a thin collagenous encapsulation tissue forms. If the material
is an irritant, inflammation will occur and this will ultimately
result in granulation tissue formation. In the case of ceramic
materials such as calcium hydroxyapatite, there is excellent
biocompatibility resulting in tissue cell growth directly on the
surface of the particles with a minimum of, or substantially no
encapsulation.
[0063] Autogenous tissue is defined herein as any tissue at a
specific defined location in the body, whose growth is stimulated
by the presence of the matrix of the biocompatible augmentation
material at the site where soft tissue augmentation is desired.
Such autogenous tissue from augmentation in the area of the
urethral sphincter would resemble existing tissue in the urethral
sphincter. Autogenous tissue from augmentation in the larynx would
resemble existing tissue in the glottis where the vocal apparatus
of the larynx is located. Autogenous tissue from breast
augmentation would resemble existing tissue in the mammaries, and
so on. Autogenous tissue in the case of intradermal injections
would resemble the dermis. In a similar manner, the augmentation
material, by providing a three dimensional lattice can be used in
surgical incisions or trauma to avoid linear, layered contractile
scar formation.
[0064] As discussed above, the calcium hydroxyapatite particles
used as the augmentation material are biocompatible and
substantially non-resorbable. Thus, the soft tissue augmentation
procedure is permanent. Moreover, the use of calcium hydroxyapatite
does not require the strict rigorous precautions that are necessary
when using other augmentation materials such as collagen which need
refrigeration for storage, shipping and antigenicity testing.
[0065] The rounded, spherical smooth calcium hydroxyapatite
particles enhance the biocompatibility to the autogenous tissue
response into the particle matrix and substantially eliminates the
potential for calcification. Jagged or irregular particles can
irritate tissue and can cause calcification. In addition, surface
porosity on the order of about 30 volume % or greater can also
cause calcification because of the relative stability of the pores
in the particles. Smooth round, substantially non-porous particles
maintain movement in the tissue. Thus, the autogenous tissue grown
in the particle matrix where movement is maintained, does not
calcify. In contrast, the porous sections of the individual
particles are stationary relative to the particle, thus tissue
infiltration into the pores is not subject to movement and
calcification can occur.
[0066] The particulate ceramic material can be suspended in a
biocompatible, resorbable lubricant, such as a polysaccharide gel
to improve the delivery of the augmentation material by injection
to the tissue site where augmentation is desired. Suitable
polysaccharides will be readily apparent to one skilled in the art.
Polysaccharides that may be utilized in the present invention
include, for example, any suitable polysaccharide within the
following classes of polysaccharides: celluloses/starch, chitin and
chitosan, hyaluronic acid, hydrophobe modified systems, alginates,
carrageenans, agar, agarose, intramolecular complexes,
oligosaccharide and macrocyclic systems. Examples of
polysaccharides grouped into four basic categories include: 1.
nonionic polysaccharides, including cellulose derivatives, starch,
guar, chitin, agarose and dextron; 2. anionic polysaccharides
including cellulose derivatives starch derivatives, carrageenan,
alginic acid, carboxymethyl chitin/chitosan, hyaluronic acid and
xanthan; 3. cationic polysaccharides including cellulose
derivatives, starch derivatives guar derivatives, chitosan and
chitosan derivatives (including chitosan lactate); and 4.
hydrophobe modified polysaccharides including cellulose derivatives
and alpha-emulsan. Preferred polysaccharides for use in the present
invention include, for example, agar methylcellulose, hydroxypropyl
methylcellulose, ethylcellulose, microcrystalline cellulose,
oxidized cellulose, chitin, chitosan, alginic acid, sodium
alginate, and xanthan gum.
[0067] The cellulose polysaccharide gels are particularly
advantageous because of what can be referred to as their
viscoelastic characteristics. Among these characteristics is that
of shear thinning. That is, the cellulose polysaccharide gels will
flow more readily as forces are applied thereto. This facilitates
the ease of mixing when the solid granulate is added to the gel.
The shear thinning also permits an easier delivery of the viscous
material than would otherwise be the case. Another characteristic
of the material is that it is elastic in that it tends to recover
its initial shape after being deformed. This is highly significant
because the elastic nature of the gel allows for the gel to suspend
the augmentation material substantially indefinitely therefore
achieving a substantially indefinite shelf life. Materials of
relatively high density may be suspended by this gel. For example,
calcium hydroxylapatite granulate, spherically shaped with
diameters ranging from 75 to 125 micrometers, and with a density of
3.10 g/cc can be indefinitely suspended in a gel with a composition
of 14.53 parts glycerin, 82.32 parts water, and 3.15 parts
NaCMC.
[0068] The elastic characteristics of the gel in accordance with
the present invention are further advantageous because the tissue
augmentation material and the cellulose polysaccharide gel can be
subjected to mixing to suspend the tissue augmentation material in
the gel using conventional mixing apparatus without adverse impact
on the gel carrier. That is, the gel carrier will not break down or
lose its elastic properties. These processes are enhanced by the
rate of recovery of gel elastic properties which occurs in a matter
of seconds once the hydrated gel has been formed. This rapid
recovery of shape due to the elasticity is also highly significant
for placement and retention of the material when implanted into
living tissue. The recovery of a more viscous characteristic, once
the force of injection is removed, assists in the retention in
place of the material, minimizing extravasation.
[0069] Any suitable solvent for the cellulose polysaccharide gel
may be utilized in the present invention. For example, the gel may
be an aqueous cellulose polysaccharide gel. Alternatively, the
solvent may be an aqueous alcohol, including for example, glycerol,
isopropyl alcohol, ethanol, and ethylene glycol, or mixtures of
these. Other suitable solvents for the gel carrier will be apparent
to one skilled in the art. Surfactants, stabilizers, pH buffers,
and other additives may also be useful, as would be obvious to one
skilled in the art. Pharmaceutically active agents, such as growth
factors, antibiotics, analgesics, etc. could also be usefully
incorporated and would be apparent to one skilled in the art.
[0070] In addition, while the present invention has been described
herein with respect to a ceramic tissue augmentation material, the
cellulose polysaccharide gel carrier of the present invention may
also be utilized as a carrier for other tissue augmentation
material. For example, the cellulose polysaccharide gel carrier of
the present invention may be utilized as a carrier for non-ceramic
tissue augmentation material such as, glass,
polymethyhnethacrylate, silicone, titanium and other metals, etc.
Other suitable non-ceramic tissue augmentation material that may be
suspended using the carrier of the present invention will be
apparent to one skilled in the art.
[0071] The formulation of the gel will depend on a number of
factors, including: 1) the molecular weight, degree of
substitution, and other properties of the polysaccharide, 2) the
solvent system employed, and 3) final properties required for the
particular application of the material. In general, the ratio of
cellulose polysaccharide to solvent can vary from about 0.5 to 10:
95.5 to 90. For example, in an 85:15 water:glycerin mixture, the
ratio is preferably about 1.5 to 5: 98.5 to 95, and most preferably
about 2.5 to 3.5: 97.5 to 96.5, respectively.
[0072] Preferably, the gel comprises water, glycerin and sodium
carboxymethylcellulose. The gel enables the ceramic particles to
remain in suspension without settling for an indefinite period of
time until used, more specifically, at least about 6 months. Other
suitable lubricant compositions known in the art can also be
employed.
[0073] In general, the ratio of water (or other solvent, e.g.
saline, Ringer's solution, etc.) to glycerin in the gel can vary
from about 10 to 100:90 to 0, preferably about 20 to 90:80 to 10,
and most preferably about 85:15, respectively.
[0074] The viscosity of the gel can vary from about 20,000 to about
350,000 centipoise, preferably about 150,000 to about 250,000
centipoise, and more preferably from greater than 200,000 to about
250,000 centipoise as measured with a Brookfield Viscometer with
RU#7 spindle at 16 revolutions per minute (rpm) at 25.degree. C. It
has been found that with gel viscosities below about 20,000
centipoise the particles may not remain in suspension, and with gel
viscosities above about 350,000 centipoise, the gel may become too
viscous for convenient mixing.
[0075] In a preferred embodiment of the invention wherein the
polysaccharide is sodium carboxymethylcellulose, the sodium
carboxymethylcellulose included in the gel has a high viscosity.
More specifically, the sodium carboxymethylcellulose preferably has
a viscosity of about 1000 to 4000 centipoise, preferably about 2000
to 3000 centipoise, in a 1% aqueous solution per a procedure given
in Hercules/Agualon Division Brochure 250-10F EV. 7-95 2M, "Sodium
Carboxymethylcellulose Physical and Chemical Properties," pp.
26-27. The carboxymethylcellulose content can vary from about 0.25
to 5 weight %, preferably 2.50 to 3.50% of the combined (85 parts)
water and (15 parts) glycerin in the gel.
[0076] The cellulose polysaccharide gel carrier of the present
invention has been discussed in connection with the preferred
sodium carboxymethylcellulose gel carrier. However, as discussed
above, any suitable polysaccharide gel may be utilized for the
carrier in accordance with the present invention, provided it
suspends the tissue augmentation material homogeneously therein for
a substantially indefinite period of time and possesses the shear
thinning and elastic properties described above. More specifically,
the polysaccharide gel carrier preferably has the following shear
thinning and elastic properties: 1) a viscosity of between 1 and 5
million centipoise when stressed with a shear of 200 Pascals and a
viscosity of 300,000 to 1 million cps when stressed with a shear of
500 Pa; 2) an elastic modulus, under a 100 Pa. maximum force
measured at 1 hertz, of 50 to 1000 Pa.; 3) a ratio of viscous
modulus to elastic modulus of 0.2 to 1.0, when measured under a 100
Pa. maximum force at 1 hertz; 4) a recovery of deformation of 5 to
75% after being subjected to a deformation force of 100 Pa for 120
seconds; and, 5) a majority of the recovery of the deformation in
(4) should occur in 2 to 10 seconds. The measurements described
above can be conducted with a controlled stress rheometer, e.g. a
Hake RS100 with a 2 cm. parallel plate, operating in stress ramp,
oscillatory, and creep/recovery modes. The actual values of the
shear thinning and elastic properties described above will depend
on the intended application and properties (e.g. size, density,
etc.) of a dispersed particulate.
[0077] In the tissue augmentation material and method of the
present invention, other polysaccharides can also be included or
used separately such as cellulose, agar methylcellulose,
hydroxypropyl methylcellulose, ethylcellulose, microcrystalline
cellulose, oxidized cellulose, chitin, chitosan, alginic acid,
sodium alginate, xanthan gum and other equivalent materials.
[0078] Unexpectedly, formulating the augmentation particles of the
present invention, particularly the calcium hydroxyapatite with
sodium carboxymethylcellulose, provides a change in the surface
morphology of the particles which is believed to enhance the
physical and biocompatible properties of the material.
[0079] The glycerin in the preferred formulation provides several
advantages. First, the composition is more lubricious when glycerin
is present. Second, for a given level of polysaccharide gel former,
the viscosity is substantially enhanced with some glycerin relative
to a pure aqueous gel. Third, the presence of the glycerin
minimizes moisture loss of the gel by dessication.
[0080] The gel is prepared by mixing the gel components at ambient
conditions until all components are in solution. It is preferable
to is combine the glycerin and NaCMC components together first
until a thoroughly mixed solution is obtained. The glycerin/NaCMC
solution is then mixed together with the water until all components
are in solution to form the gel. After the gel components have been
thoroughly mixed, the gel is allowed to set for a minimum of 4
hours, after which viscosity readings are taken to ensure that the
gel has the desired viscosity.
[0081] While any lubricant or carrier can be employed, it has been
found that certain materials, e.g., polysorbate surfactants,
pectin, chondroitin sulfate and gelatin, are not able to suspend
the ceramic particles for an indefinite amount of time and allow
further processing or be as easy to inject in the same manner as
the preferred sodium carboxymethylcellulose. Thus, the sodium
carboxymethylcellulose materials are preferred.
[0082] The preferred polysaccharide gel is biocompatible and able
to maintain the particles of ceramic material in what amounts to a
substantially permanent state of suspension so that the ceramic
particulate/gel composition comprising the augmentation material
does not require mixing before use. As already noted, the
lubricious nature of the polysaccharide gel reduces the frictional
forces generated by transferring the augmentation material from a
syringe by injection into the tissue site.
[0083] In addition, the polysaccharides do not generate an
antigenic response as do products containing amino acids. The
polysaccharide gel is readily sterilizable and stable at ambient
conditions and does not need refrigeration for storage and
shipment, in contrast to systems used with collagen containing
materials.
[0084] Sterilization is ordinarily accomplished by autoclaving at
temperatures on the order of about 115.degree. C. to 130.degree.
C., preferably about 120.degree. C. to 125.degree. for about 30
minutes to 1 hour. Gamma radiation is unsuitable for sterilization
since it tends to destroy the gel. It has also been found that
sterilization generally results in reduction of its viscosity.
However, this does not adversely affect the suspension and
therefore the extrusion force of the augmentation material through
a syringe, nor does it affect the ability of the gel to hold the
calcium hydroxyapatite particles in suspension, as long as the
prescribed viscosity ranges for the gel are maintained.
[0085] After injection of the augmentation material into the
tissue, the polysaccharide gel is harmlessly resorbed by the
tissue, leaving the nonresorbable calcium hydroxyapatite matrix in
place in the particular area or bolus, where it has been found to
remain without migrating to other areas of the body. It generally
takes an average of about 2 weeks for the polysaccharide to
completely resorb.
[0086] FIG. 2 shows a histological section of rabbit 10 tissue at
50.times. magnification which has been infiltrated with autogenous
three dimensional, randomly oriented, non-scarring soft muscle
tissue as a result of an injection of calcium hydroxyapatite
particles having a uniform particle size distribution of 38 to 63
microns. The photomicrograph shows growth after 12 weeks. The
histological section also demonstrates the biocompatibility of the
calcium hydroxyapatite as the cells grow on the surface of the
particles with minimal or substantially no foreign body
response.
[0087] It has been found that the amount of calcium hydroxyapatite
particles in the augmentation material can vary from about 15% to
50% by volume, and preferably about 25% to 47.5% and most
preferably about 35% to 45% by volume of the total augmentation
material, comprising the gel and the ceramic particles.
[0088] Preparations having above 50 volume % ceramic particles
become viscous and care should be taken as to the selection of
injection apparatus. As a lower limit the augmentation material of
this invention should obviously contain a sufficient volume of
ceramic particles to provide an effective base for autogenous
tissue growth. For most applications this is at least 15 volume %.
By maintaining a volume % of about 35 to 45%, a correction factor
of about 1:1 can be achieved, that is, the volume of autogenous
tissue growth is roughly equivalent to the volume of particles
introduced and shrinkage or expansion at the site of the soft
tissue augmentation does not generally occur.
[0089] Also, within these parameters, the augmentation material can
easily be injected through an 18 gauge or smaller syringe
intradermally or subcutaneously. Because of the reduced frictional
forces necessary to deliver the biocompatible augmentation material
by injection to the desired tissue site, the size of the syringe
used to transfer or inject the biocompatible augmentation material
can be significantly reduced. This substantially eliminates the
possibility of creating a needle trail through which leakage of the
augmentation material from the injection site can occur after
withdrawing the injection needle. Thus, the syringes used to inject
the augmentation material can have reduced openings of less than
1,000 microns in diameter to a minimum of about 178 microns or
less.
[0090] For example, an 18 gauge syringe having a diameter of about
838 microns, or a 20 gauge syringe having a diameter of about 584
microns, or a 22 gauge syringe having a diameter of about 406
microns, and even a 28 gauge syringe having a diameter of about 178
microns can be used, depending on the tissue site where
augmentation is needed.
[0091] The lubricious suspension of augmentation material is
prepared by simply mixing the desired amount of ceramic particles
with the lubricious gel until a uniform, homogeneous suspension is
reached. The consistency of the ceramic particles suspended in the
lubricious gel is comparable to strawberry preserves, wherein the
seeds and other solid parts of the strawberry, for all practical
purposes, are comparable to the ceramic particles and remain
substantially permanently suspended in the jelly preserve
matrix.
[0092] The suspension of ceramic material in the lubricious gel is
so stable, that centrifugation at forces on the order of 500 g's,
that is, 500 times the force of gravity generally do not affect the
stability of the suspension or cause it to settle out. The
tendency, if any, for particles to settle out over a period of time
would appear more likely to occur with the larger particle sizes on
the order of 125 microns or larger. Thus, remixing the augmentation
material at the time of injection or implantation is ordinarily not
necessary. In addition, the polysaccharide gel lubricates the
suspended ceramic particles so that the injection force on the
syringe can be minimized when injecting the augmentation
material.
[0093] Tissue augmentation material in accordance with the present
invention is particularly advantageous in the treatment of
osteoporosis or related pathologies in, for example, the femur, or
osseous defects due to trauma or surgical incision. The advantages
of this material in these applications include biocompatibility,
ease of application, and a superior result to other materials
currently employed.
[0094] Specifically, because the material can be injected through
fine catheters and needles, small incision sites such as less than
a 4.5 mm hole in the bone site may be used, resulting in minimizing
the immediate loss of bone trabeculae--the opposite of the intended
longer term result. Because of the smaller needle required for
using tissue augmentation material in accordance with the present
invention, the hole diameter could be greatly reduced and the depth
could also be greatly reduced.
[0095] Particles are held together in the present invention for
some time by the gel carrier, even in a liquid environment. In an
osseous site, the gel would provide a means of "fixing" the
particles for a period of time.
[0096] Furthermore, because the particulate is relatively small, it
is distributed more widely in the site of interest via injection.
The viscosity of the gel carrier could be tailored to produce
either a "thin, runny" consistency media or a "thick, robust"
consistency, as desired. This could be done by modifying the
content of the other components of the composition including, for
example, glycerin and sodium carboxymethylcellulose.
[0097] The particle size of the ceramic particulate in the tissue
augmentation material could be reduced for this application. That
is, material which could be used would be a 37-63 .mu.m CaHA
particulate. The main advantage of a larger size range of particle
sizes in soft tissue is to ensure a lack of migration due to
cellular mechanisms that could transport the particulate to distant
organ sites. The chance of this occurring, however, would be
greatly reduced for particulate contained, for example, within a
trabecular bone cavity. Also, the fact that CaHA is known to bond
to bone further reduces concern of migration.
[0098] Also, it has been discovered that tissue augmentation
material in accordance with the present invention can be the basis
for a unique material useful in implant applications. Specifically,
it has been discovered that if tissue augmentation material in
accordance with the invention is allowed to dry by exposure to air,
it developed some surprising properties. If extruded from a
syringe, either directly or through a needle or catheter, a
"string" of particles with surprising cohesion and flexibility
would result after exposure to air. It was apparent that the
material was substantially dehydrated and it is possible to form
the material in various shapes or into sheets, as desired. The
material may be molded and shaped like clay or carved into shape
with appropriate instruments to prepare a preform for implantation.
The advantages of this material include cohesion, moldability, and
the high concentration of particulate per unit volume.
[0099] The following examples show specific embodiments of the
invention. All parts and percentages are by weight unless otherwise
noted.
EXAMPLES
Example 1
[0100] Preparation of The Gel
[0101] A mixture of 15% glycerin, 85% water, (based on the combined
weight of the water and glycerin) and 3.25% NaCMC (again based on
the total of the liquid components) is prepared in the following
manner:
[0102] 9.303 g of glycerin and 2.016 g of NaCMC are combined in a
vessel. The mixture is then slowly added to 52.718 g of agitating
water in a container large enough for batch size and allowed to
mix, utilizing an electric mixer, for 30 minutes at a medium speed.
The gel is allowed to set for a minimum of four hours.
Example 2
[0103] Preparation of the Augmentation Composition
[0104] Aqueous glycerin/NaCMC gel (44.04 g, prepared in Example 1)
are placed in a mixing container large enough for batch size.
Smooth, rounded substantially spherical CaHA particles (55.99 g)
having a uniform particle size of 75 to 125 microns are thoroughly
blended, utilizing an electric mixer, for five minutes at a low
speed until all the particles are homogeneously distributed in a
uniform suspension in the gel. The blended material is packaged in
3 cc polysulfone cartridges and sterilized in an autoclave for 60
minutes at 121.degree. C.
Example 3
[0105] Properties of Augmentation Composition
[0106] The gel as prepared in Example 1, and the augmentation
medium as prepared in Example 2 are examined by means of a parallel
plate rheometer (Hake RS 100). Testing includes the measurement of
rheological properties as a function of applied stress (stress
ramp), deformation at constant stress followed by recovery at 0
stress (creep/recovery), and the measurement of the complex modulus
using an oscillating stress within the viscoelastic limit of the
composition (frequency sweep). Outcomes demonstrate that the
behavior of the gel and augmentation composition, both before and
after sterilization, is the same. For example, this is demonstrated
in FIG. 3, which shows the viscosity of the gel and augmentation
material before and after sterilization as a function of applied
stress from 10 to 1000 Pascals. The shape of the curves are similar
and demonstrate the shear thinning characteristic of this material.
Other measured values are given in the following table. The
viscosity is determined at 500 Pa in a stress ramp measurement. The
elastic modulus is determined under an oscillating force of 100 Pa
at 1 hertz. The ratio of the inelastic modulus to elastic modulus,
tan .delta., is determined under an oscillating force of 100 Pa at
1 hertz. The maximum deflection, .delta. max' is determined after
120 seconds of a constant 100 Pa applied stress. The % Recovery is
determined after a relaxation of 200 seconds following 120 seconds
of a constant 100 Pa applied stress.
1TABLE 1 Rheological results of gel and augmentation materials
taken on a Hake RS100 control stress rheometer using 2 cm. parallel
plates. As Prepared Sterilized As Prepared Augmentation
Augmentation Gel Composition Composition Viscosity (Cp) @ 603,000
4,610,000 4,340,000 500 Pa stress Elastic Modulus 408 2520 2684
(100 Pa @ 1 Hz) tan .delta. (100 Pa @ 0.461 0.453 0.429 1 Hz)
.gamma. max 2.227 0.367 0.345 % Recovery 44.99 45.50 46.96
Example 4
[0107] Preparation of the Gel
[0108] A mixture of 25% glycerin, 75% water, and 2.25% NaCMC (based
on the combined weight of the water and glycerin) is prepared in
the following manner:
[0109] 87.90 g of glycerin and 7.91 g of NaCMC are combined in a
vessel large enough to mix the total mass. The mixture is then
slowly added to 263.71 g of agitating water in a container large
enough for batch size and allowed to mix, utilizing an electric
mixer, for 30 minutes at a medium speed. The gel is allowed to set
for a minimum of four hours.
Example 5
[0110] Preparation of the Augmentation Composition
[0111] Aqueous glycerin/NaCMC gel (38.52 g, prepared in Example 1)
are placed in a mixing container large enough for batch size,
Smooth, rounded substantially spherical CaHA particles (74.86 g)
having a uniform particle size of 37 to 63 microns are thoroughly
blended, utilizing an electric mixer, for five minutes at a low
speed until all the particles are homogeneously distributed in a
uniform suspension in the gel.
Example 6
[0112] In most instances it takes relatively little force to inject
or extrude the augmentation composition, comprising the
polysaccharide gel/particulate calcium hydroxyapatite suspension,
into the air since there is relatively little resistance. However,
greater forces were necessary to inject the augmentation
composition into tissue, and this force is significantly influenced
by the shape of the particulate material. This was exemplified by
preparing sterilized suspensions of polysaccharide gel made of 75%
water, 25% glycerin, and 2.25% sodium carboxymethylcellulose (based
on the combined weight of the water and glycerin) with various
volume percents of calcium hydroxyapatite particles having
different shapes, following the procedure of Example 2. The thus
prepared suspensions were placed in standard 3 cubic centimeter
syringes. The force applied to the plunger to extrude the
polysaccharide gel/particulate suspension at a rate of one inch per
minute through an 18 gauge needle was then measured. The force was
also measured with the needle inserted into turkey gizzard tissue
as an analogy as it would be used clinically. The spray dried
particles of calcium hydroxyapatite, regardless of their shape, had
a smooth, uniform appearance under microscopic examination at
40.times. magnification. The particles were uniformly distributed
within the range of particle sizes. The results are tabulated in
Table 2, which follows:
2 TABLE 2 Calcium Hydroxyapatite Particles in the Gel Size, Volume,
Force, lbs Microns Particle Shape % Solids Air Tissue 38 to 63
Spherical/Smooth 35 4.5 6.0 38 to 63 Spherical/Smooth 40 5.9 7.2 38
to 63 Irregular 40 8.0* 9.6* 74 to 100 Irregular/Smooth 37 5.5
>30 74 to 100 Irregular/Smooth 41 >30 >30 74 to 100
Spherical/Smooth 42 4.8 5.5
[0113] *Average Inconsistent results due to complete obstruction of
needle that sporadically occurred during the tests, requiring
replacement of needle.
[0114] This data correlated with animal experimentation where it
was not possible to inject irregular particles into tissue even
when the percent solids were reduced below 25 volume % or a 16
gauge needle was used.
Example 7
[0115] Sterilized samples of polysaccharide gel/particulate calcium
hydroxyapatite suspensions were prepared using a series of
designated particle size ranges. The distribution of particles was
uniform within each range of particle sizes. The particles were
smooth, round calcium hydroxyapatite, and the gel had the same
constituency as Example 1. The calcium hydroxyapatite particles
occupied 36 volume % of the suspension. The extrusion force into
the air for each suspension containing each designated range of
particle sizes was measured using a standard 3 cubic centimeter
syringe in the same manner as in Example 6. The results are
tabulated in Table 3, which follows, and demonstrate that little
difference in the extrusion force occurs as the particle size
increases, as long as the particle sizes are uniform and maintained
in a narrow distribution range.
3 TABLE 3 Size Distribution, Extrusion Force, microns lbs 40-60 2.3
62-74 2.0 40-74 2.6 82-100 2.3 100-125 2.2 125-149 2.4 100-149
2.4
Example 8
[0116] Sodium carboxymethylcellulose, water and glycerin in various
weight percents were formulated into four different gels following
the procedure of Example 1, except for the use of different
proportions. Each gel was then blended with about 40 volume %
calcium hydroxyapatite particles having a distribution of 38 to 63
microns. The gel/particle blends were then placed in standard 3
cubic centimeter syringes fitted with 18 gauge, 20 gauge and 22
gauge needles. The extrusion force of the blend into the air was
measured in the same manner as in Example 3. The results appear
below in Table 4.
4TABLE 4 Weight % Force, lbs % NaCMC* Glycerin Water 18 gauge 20
gauge 22 gauge 1.0 60 40 3.6 6.4 7.7 1.5 50 50 4.0 5.8 8.2 2.0 30
70 4.1 6.3 7.7 2.0 40 60 4.8 7.0 9.2 *Sodium
carboxymethylcellulose. Weight % of sodium carboxymethylcellulose
based on total weight of glycerin and water.
Example 9
[0117] Preparation of the Augmentation Composition
[0118] Using Polystyrene Microbeads
[0119] A gel consisting of 4.93% glycerin, 93.60% water, and 1.48%
NaCMC was prepared by methods described in Example 1. Spherical
polystyrene beads (12.79 g), having a particle size range of 100 to
500 microns are thoroughly blended, utilizing an electric planetary
mixer, for five minutes at a low speed until all the particles are
homogeneously distributed in a uniform suspension in 28.43 grams of
gel. The polystyrene beads have a density of 1.07 g/cc as measured
by helium pycnometry. The blended material is packaged in 10 cc
polypropylene syringe cartridges and sterilized in an autoclave for
60 minutes at 121.degree. C. The polystyrene beads remained
homogeneously distributed within the gel carrier. Rheologic
properties were measured as described in Example 3. The viscosity
is determined at 100 Pa in a stress ramp measurement. The elastic
modulus is determined under an oscillating force of 20 Pa at 1
hertz. The ratio of the inelastic modulus to elastic modulus, tan
.delta., is determined under an oscillating force of 20 Pa at 1
hertz. The maximum deflection, .gamma. max' is determined after 120
seconds of a constant 10 Pa applied stress. The % Recovery is
determined after a relaxation of 200 seconds following 120 seconds
of a constant 10 Pa applied stress. Results are shown in Table
5.
5TABLE 5 Rheological results of gel and polystyrene augmentation
material taken using a Hake RS100 control stress rheometer using 2
cm. parallel plates. As Prepared Sterilized As Prepared
Augmentation Augmentation Gel Composition Composition Viscosity
(Cp) @ 2,050 47,900 9,630 100 Pa stress Elastic Modulus 11 31 16
(20 Pa @ 1 Hz) tan .delta. (20 Pa @ 1.348 1.320 2.067 1 Hz) .gamma.
max. (@ 10 Pa.) 27.406 5.717 47.873 % Recovery 22.4 23.4 1.6
Example 10
[0120] Preparation of the Augmentation Composition
[0121] Using Polymethylmethacrylate Microbeads
[0122] A gel consisting of 9.80% glycerin, 88.24% water, and 1.96%
NaCMC was prepared by methods described in Example 1. Spherical
polymethylmethacrylate beads (12.78 g), having a uniform particle
size of 100 to 180 microns are thoroughly blended, utilizing an
electric planetary mixer, for five minutes at a low speed until all
the particles are homogeneously distributed in a uniform suspension
in 28.84 grams of gel. The polymethylmethacrylate beads have a
density of 1.21 g/cc as measured by helium pycnometry. The blended
material is packaged in 10 cc polypropylene syringe cartridges and
sterilized in an autoclave for 60 minutes at 121.degree. C. The
polymethylmethacrylate beads remain homogeneously distributed
within the gel carrier. Rheologic properties were measured as
described in Example 6. The viscosity is determined at 100 Pa in a
stress ramp measurement. The elastic modulus is determined under an
oscillating force of 20 Pa at 1 hertz. The ratio of the inelastic
modulus to elastic modulus, tan .delta., is determined under an
oscillating force of Pa at 1 hertz. The maximum deflection, .gamma.
max' is determined after 120 seconds of a constant 20 Pa applied
stress. The % Recovery is determined after a relaxation of 200
seconds following 120 seconds of a constant 20 Pa applied stress.
Results are shown in Table 3.
6TABLE 6 Rheological results of gel and polymethylmethacrylate
augmentation material taken using a Hake RS100 control stress
rheometer using 2 cm. parallel plates. As Prepared Sterilized As
Prepared Augmentation Augmentation Gel Composition Composition
Viscosity (Cp) @ 58,700 482,000 22,200 100 Pa stress Elastic
Modulus 58 212 42 (20 Pa @ 1 Hz) Tan .delta. (20 Pa @ 0.785 0.705
1.934 1 Hz) .gamma. max 2.895 1.111 0.211 % Recovery 53.1 48.2
20.9
Example 11
[0123] Preparation of the Augmentation Composition
[0124] Using Glass Microbeads
[0125] A gel consisting of 14.56% glycerin, 82.52% water, and 2.91%
NaCMC was prepared by methods described in Example 1. Spherical
glass beads (30.42 g), having a uniform particle size of 30 to 90
microns are thoroughly blended, utilizing an electric planetary
mixer, for five minutes at a low speed until all the particles are
homogeneously distributed in a uniform suspension in 29.27 grams of
gel. The glass beads have a density of 2.54 g/cc as measured by
helium pycnometry. The blended material is packaged in 10 cc
polypropylene syringe cartridges and sterilized in an autoclave for
60 minutes at 121.degree. C. The glass beads remain homogeneously
distributed within the gel carrier. Rheologic properties were
measured as described in Example 3. The viscosity is determined at
500 Pa in a stress ramp measurement. The elastic modulus is
determined under an oscillating force of 100 Pa at 1 hertz. The
ratio of the inelastic modulus to elastic modulus, tan .delta., is
determined under an oscillating force of 100 Pa at 1 hertz. The
maximum deflection, .gamma. max' is determined after 120 seconds of
a constant 100 Pa applied stress. The % Recovery is determined
after a relaxation of 200 seconds following 120 seconds of a
constant 100 Pa applied stress. Results are shown in Table 7. The
sterilized augmentation material was filled into 3 cc syringe
cartridges and extruded through 3.5 inch gauge spinal needles. The
average extrusion force was 14.63 lbs. with a standard deviation of
0.09 lbs.
7TABLE 7 Rheological results of gel and glass augmentation material
taken using a Hake RS100 control stress rheometer using 2 cm.
parallel plates. As Prepared Sterilized As Prepared Augmentation
Augmentation Gel Composition Composition Viscosity (Cp) @ 135,000
803,000 569,000 500 Pa stress Elastic Modulus 256 699 570 (100 Pa @
1 Hz) tan .delta. (100 Pa @ 0.545 0.557 0.692 1 Hz) .gamma. max
4.302 1.195 3.259 % Recovery 36.3 37.7 24.7
Example 12
[0126] Preparation of the Augmentation Composition
[0127] Using Stainless Steel Microbeads
[0128] A gel consisting of 4.76% glycerin, 90.48% water, and 4.76%
NaCMC was prepared by methods described in Example 1. The mixing
time was extended from 30 minutes to one hour for this formulation.
Spherical stainless steel beads (95.19 g), having a uniform
particle size of 60 to 125 microns are thoroughly blended,
utilizing an electric planetary mixer, for five minutes at a low
speed until all the particles are homogeneously distributed in a
uniform suspension in 28.69 grams of gel. The stainless steel beads
have a density of 7.93 g/cc as measured by helium pycnometry. The
blended material is packaged in 10 cc polypropylene syringe
cartridges and sterilized in an autoclave for 60 minutes at
121.degree. C. The stainless steel beads remain homogeneously
distributed within the gel carrier. Rheologic properties were
measured as described in Example 3. The viscosity is determined at
500 Pa in a stress ramp measurement. The elastic modulus is
determined under an oscillating force of 100 Pa at 1 hertz. The
ratio of the inelastic modulus to elastic modulus, tan 6, is
determined under an oscillating force of 100 Pa at 1 hertz. The
maximum deflection, 7 max' is determined after 120 seconds of a
constant 100 Pa applied stress. The % Recovery is determined after
a relaxation of 200 seconds following 120 seconds of a constant 100
Pa applied stress. Results are shown in Table 8. The sterilized
augmentation material was filled into 3 cc syringe cartridges and
extruded through 3.5 inch 20 gauge spinal needles. The average
extrusion force was 30.84 lbs with a standard deviation of 0.37
lbs.
8TABLE 8 Rheological results of gel and stainless steel
augmentation material taken on a Hake RS100 control stress
rheometer using 2 cm. parallel plates. As Prepared Sterilized As
Prepared Augmentation Augmentation Gel Composition Composition
Viscosity (cp) @ 8,150,000 42,400,000 23,600,000 500 Pa stress
Elastic Modulus 1663 8411 5085 (100 Pa @ 1 Hz) tan 6 (100 Pa @
0.335 0.366 0.400 Hz 1) .gamma. max 0.336 0.110 0.197 % Recovery
62.8 64.5 54.3
Example 13
[0129] Preparation of the Augmentation Composition
[0130] Using a Xanthan Gum Gel Former
[0131] A gel consisting of 13.8 parts glycerin, and 78.2 parts
water, and 8 parts xanthan gum polysaccharide was prepared by
methods described in Example 1. The viscosity of the gel, measured
using a Brookfield Rheometer, was 51,250 cps. Calcium
hydroxylapatite granulate in a range of 75 to 125 microns in
diameter are thoroughly blended, utilizing an electric planetary
mixer, for five minutes at a low speed until all the particles are
homogeneously distributed in a uniform suspension in of gel. The
blended material is packaged in polypropylene syringe cartridges
and sterilized in an autoclave for 60 minutes at 121.degree. C. The
hydroxlyapatite particulate remained homogeneously distributed
within the gel carrier. Centrifugation of the cartridges in a IEC
Clinical centrifuge, Model 0M428, at a force of 1016.times. g for 5
minutes did not result in a settling of the particulate in the gel
carrier. (This result suggests that the particulated will not
settle even over an extended period of time as the elastic limit of
the gel will not be exceeded.) The augmentation material was
extruded from the syringe cartridges through 1.5 inch long 18 gauge
needles. The force required was 3.90 lbs.
Example 14
[0132] Preparation of the Augmentation Composition
[0133] Using A Xanthan Gum Gel Former and Isopropylacohol
[0134] A gel consisting of 64.4 parts isopropyl alcohol, and 27.6
parts water, and 8 parts xanthan gum polysaccharide was prepared by
methods described in Example 1. The viscosity of the gel, measured
using a Brookfield Rheometer, was 37,500 cps. Calcium
hydroxylapatite granulate in a range of 75 to 125 microns in
diameter are thoroughly blended, utilizing an electric planetary
mixer, for five minutes at a low speed until all the particles are
homogeneously distributed in a uniform suspension in of gel. The
blended material is packaged in polypropylene syringe cartridges
and sterilized in an autoclave for 60 minutes at 121.degree. C. The
hydroxylapatite particulate remained homogeneously distributed
within the gel carrier. Centrifugation of the cartridges in a IEC
Clinical centrifuge, Model 0M428, at a force of 1016.times. g for 5
minutes did not result in a settling of the particulate in the gel
carrier. (This result suggests that the particulated will not
settle even over an extended period of time as the elastic limit of
the gel will not be exceeded.) The augmentation material was
extruded from the syringe cartridges through 1.5 inch long 18 gauge
needles. The force required was 7.34 lbs.
Example 15
[0135] The gel is prepared in accordance with Example 1, and the
augmentation medium is prepared in accordance with Example 2. The
patient is then appropriately anesthetized and a hole (greater in
diameter than an 18 gauge needle) is then drilled with an entry
point in the soft cancellous part of the greater trochanter into
the neck, head and trochanteric region of the femur. An 18 gauge
needle 3.5 inches long is connected to the syringe containing the
augmentation media using the Luer lock connection. The augmentation
media is then injected through the hole in the bone. Sufficient
material is injected to serve as a scaffold for bone growth between
the particles creating osseous formation and strengthening of the
trochanter and the femoral head of the femur and thus reducing the
risk of fracture.
[0136] Although the present invention has been described in
connection with preferred embodiments thereof, many other
variations and modifications and other uses will become apparent to
those skilled in the art without departing from the scope of the
invention. It is preferred, therefore, that the present invention
not be limited by the specific disclosure herein, but only by the
appended claims.
* * * * *